Anticoagulant peptides

This invention relates to peptide derivatives which are useful anticoagulant agents.

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Claims

1. A peptide derivative of the formula

Ile-Pro-Glu-Glu-Ala-Phe-Lys-OH;
Ile-Pro-Glu-Glu-Ala-His-Lys-OH;
Ile-Pro-Glu-Glu-Ala-Cha-Lys-NH.sub.2;
Ile-Pro-Glu-Glu-Leu-Phe-Lys-NH.sub.2;
Ile-Pro-Glu-Glu-Ala-Phe-Glu-OH;
Ile-Pro-Glu-Glu-Ala-Phe-Gln-OH;
Ile-Pro-Glu-Glu-Ala-Cha-Asp-OH;
Ile-Pro-Glu-Glu-Tyr-Cha-Gln-OH;
Ile-Pro-Glu-Glu-Pro-Cha-D-Glu-OH;
Ile-Pro-Glu-Glu-Ala-Phe-Lys-NH.sub.2;
Ile-Pro-Glu-Glu-Ala-Phe-D-Lys-NH.sub.2;
Ile-Pro-Glu-Glu-Ala-Phe-Orn-NH.sub.2;
Ile-Pro-Glu-Glu-Ala-Tyr-Lys-NH.sub.2; and
Ile-Pro-Gln-Glu-Ala-Phe-Lys-NH.sub.2.

2. A peptide derivative of the formula

Suc-Npa-;
Suc-Tyr-;
Mal-Tyr-;
Glt-Tyr-; and
Fum-Tyr-.

3. A peptide derivative of the formula

-Glu-Ile-Pro-Ala-Glu-Tyr-Leu-Gln-OH;
-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-Ala-OH;
-Glu-Ile-Pro-Glu-Glu-Glu-Leu-Ala-OH;
-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-NH.sub.2;
-Pro-Ile-Pro-Glu-Glu-Ala-Tyr-Gln-OH;
-Glu-Ile-Pro-Glu-Glu-Ala-Tyr-Glu-OH;
-Glu-Ile-Pro-Glu-Asp-Ala-Tyr-Gln-OH;
-Glu-Ile-Pro-Glu-Ala-Tyr-Leu-Gln-OH;
-Glu-Ile-Pro-Glu-Glu-Ala-Leu-Gln-OH; and
-Pro-Ile-Pro-Glu-Glu-Tyr-Tyr-Gln-OH.

4. A peptide derivative selected from the group consisting of:

Suc-Phe-Glu-Pro-Ile-Pro-Glu-Glu-Tyr-Leu-Pro-NH.sub.2;
Suc-Phe-Glu-Pro-Ile-Pro-Glu-Glu-Pro-OH;
Ac-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-Orn-NH.sub.2;
Suc-Cha-Glu-Pro-Ile-Pro-Glu-Glu-Pro-Cha-D-Glu-OH;
Suc-Tyr-Glu-Pro-Ile-Pro-Glu-Glu-Ala-Cha-D-Glu-OH; and
Suc-Phe-Glu-Pro-Ile-Pro-Glu-Asp-Ala-Tyr-Pro-NH.sub.2.
Referenced Cited
U.S. Patent Documents
4499082 February 12, 1985 Shenvi et al.
4638047 January 20, 1987 Szelke et al.
4654302 March 31, 1987 Fritz et al
4668662 May 26, 1987 Triper
4737487 April 12, 1988 Watts et al.
4745177 May 17, 1988 Fritz et al.
4767742 August 30, 1988 Dodt et al
5192747 March 9, 1993 Krstenansky
5541161 July 30, 1996 Krstenansky et al.
Foreign Patent Documents
B.30225633 June 1987 EPX
B.40276014 July 1988 EPX
B.63445517 June 1986 DEX
B.53445532 June 1986 DEX
Other references
  • Dayhoff, Atlas of Preotein Sequence and Structure vol. 5 pp. 89-99, 1972. J.L. Krstenansky et al., Peptides: Chemistry and Biology; Tenth American Peptide Symposium, St. Louis, Missouri, May 23-28 (1987), Escom Science Publishers B.V.: Leiden, Netherlands, pp. 447-448. Baskova, et al., Thrombosis Research 30:459-467 (1983). Markwardt, Biomed. Biochim. Acta 44:1007-1013 (1985). Huzoor-Akbar, et al., Haemostasis 6:59-71 (1977). Hoffman, et al., Haemostasis 14:164-169 (1984). Minar, et al., Klin Wochenschr 63:190-191 (1985). Hastabacka, et al., Nordisk Medicin 6:444-445 (1967). Budzynski, et al., Proceedings of the Society for Experimental Biology and Medicine 168:266-275 (1981). Markwardt, et al., Thromb Haemostas (Stuttgart) 52(2):160-163 (1984). Markwardt, et al., Thromb Haemostas (Stuttgart) 47(3):226-229 (1982). Wu, et al., Thrombos Haemostas (Stuttg.) 35:702-711 (1976). Brown, et al., Thrombosis Research 17:267-272 (1980). Markwardt, et al. Thrombosis Research, vol. 11:275-283 (1977). Ishikawa, et al, Thrombosis Research 19:351-358 (1980). Neal, et al., Thrombosis Research 16:473-484 (1979). Krstenansky, et al., Peptides: Chemistry and Biology; Tenth American Peptide Symposium, St. Louis,Missouri, May 23-28, (1987) Escom Science Publishers B.V.: Leiden, Netherlands. p. 447. Krstenansky, et al., Thrombosis Research 52:137-141 (1988). Krstenansky, et al., Thrombosis Research 54:319-325 (1989). Krstenansky et al., Thrombosis and Haemostasis (Stuttgart) 63(2):208-214 (1990). Krstenansky et al., Chemical Abstracts 109:231560t, p. 918 (1988). Markwardt, et al., Thromb. Haemost 49(3):235-237 (1983). Owen, T.J., J. Med. Chem., 1009-1011 (1988). Mao et al., Analytical Biochemistry, vol. 161, pp. 514-518 (1987). Cram et al., Organic Chemistry, 2.sup.nd Edition, McGraw-Hill Book Company, New York, pp. 607-613 (1964). Lehninger, Principles of Biochemistry, 2.sup.nd Edition, Worth Publishers, Inc., New York, pp. 95-117 (1982). Robson et al., Introduction to Proteins and Protein Engineering, Elsevier Science Publishers B.V., New York, pp. 323-325 (1986). Bajusz et al. Peptides 32, pp. 473-476 (1984). Chang FEBS vol. 164 pp. 307-313. (1983). Rudinger, Peptide Hormone, Parsons (Edi), U. Park Press, Baltimore pp. 1-7 (1976). Krstenansky et al, J. Med. Chem. vol. 30 No. 9 pp. 1688-1691 (Sep., 1987). J.L. Krstenansky, et al., FEBS Lett. 211(1) 10-16 (1987).
Patent History
Patent number: 5789540
Type: Grant
Filed: Mar 28, 1995
Date of Patent: Aug 4, 1998
Assignee: Merrell Pharmaceuticals Inc. (Cincinnati, OH)
Inventors: John L. Krstenansky (Cincinnati, OH), Simon J. T. Mao (Loveland, OH)
Primary Examiner: Sheela Huff
Attorney: T. Helen Payne
Application Number: 8/412,356